Background

Calcium–calmodulin-dependent protein kinase II (CaMKII) is a major synaptic protein. This kinase is a large holoenzyme consisting of 12 subunits. There are two types of subunits (alpha and beta) both of which are capable of catalysis. Recent work has led to crystallization of the holoenzyme and the elucidation of how the enzyme’s structure relates to its function. The kinase can act as a protein switch; once activated by calcium–calmodulin, the enzyme can be autophosphorylated at T286 (on the alpha subunits; 287 on the beta subunits), an event that makes CaMKII activity persist even after the calcium concentration falls to baseline levels (the T286 autophosphorylated state of CaMKII is termed the ‘autonomous’ state). If active CaMKII subunits or holoenzymes are introduced into CA1 neurons, the EPSC becomes large and LTP can no longer be induced by synaptic stimulation. If persistent activation of CaMKII is prevented by a knock-in mutation encoding T286A in CaMKII, LTP induction is prevented and mice show profound memory impairments, notably after one-trial learning. In many mutants with enhanced learning, CaMKII activation is enhanced.

Calcium (Ca2+) signaling regulates a variety of cellular processes including secretion, contraction, carbohydrate metabolism, gene expression, neuronal plasticity, and cell cycle progression. Multifunctional Ca2+/calmoduiin-dependent protein kinase, or CaM Kinase II (CaMKII), is one of the key mediators of Ca2+ signal transduction. Several cell-type specific substrates of CaMKII have been identified, including transcription factors; synapsin I, AMPA-type glutamate receptors, and tyrosine hydroxylase in neuronal cells; myosin light chain kinase in smooth muscle cells; Troponin T in skeletal muscle; and Troponin I in skeletal and cardiac muscle cells. While CaMKII activity has been well studied in neuronal signaling, the role of CaMKII in the regulation of cell cycle progression is less well understood.

Previous studies have implicated a role for CaMKII at multiple points in the cell cycle, including the G1/S, G2/M, and metaphase/anaphase transitions. However, the requirement for CaMKII appears to be cell type-specific. In HeLa cells, a specific inhibitor of CaMKII, KN-93, inhibits proliferation and causes a G (/S block to cell cycle progression. In contrast, expression of constitutive CaMKII mutants caused a cell cycle arrest at the G2/M border in both a mammalian cell line C l27 and the yeast, 5. pombe. Interestingly, the effect of CaMKII on p34cdc2, the mitosis promoting factor, was not conserved. In mouse C l27 cells, constitutive CaMKII triggered increased p34cdc2 activity. These cells exhibited an interphase phenotype characterized by uncondensed chromatin, intact nuclear envelopes and distinct nucleoli. Genetic analysis of S. pombe, however, suggested that CaMKII blocked cell cycle progression prior to cdc2 activation.

CaMKII activity is required for nuclear envelope breakdown in sea urchin embryos. Following sea urchin fertilization, the male and female pronuclei fuse, and DNA replication is completed, prior to nuclear envelope breakdown. Inactivation of CaMKII by injections of specific inhibitors or antibodies blocked nuclear envelope breakdown at both the 1 and 2 cell stages, suggesting that CaMKII is necessary for nuclear envelope breakdown and mitosis. In Xenopus, CaMKII plays important roles in the release of meiotic metaphase II arrest following fertilization of eggs. Activation of eggs, by sperm or pin prick, triggers a surge of intracellular calcium which activates CaMKII. Studies of egg extracts indicate that CaMKII triggers the ubiquitin-dependent degradation of cyclin B 1 and Mos. Microinjection of a CaMK II inhibitory peptide into unfertilized eggs blocks ceil cycle progression in response to parthenogenetic activation, demonstrating that CaMKII activity is necessary for metaphase release in vivo. Furthermore, CaMKII plays an active role in the separation of sister chromatids at the onset of anaphase.

Reference:EMILY LOUISE HOWARD. THE ROLE OF THE MAP KINASE SIGNALING PATHWAY IN THE REGULATION OF MOS GENE EXPRESSION DURING XENOPUS OOCYTE MATURATION